Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) - dependent, slowly progressive optic neuropathy that ultimately leads to blindness. Our prior work suggests that impaired nitric oxide (NO) signaling, exacerbated by declining estrogen levels contributes to dysfunctional endothelial cell - smooth muscle communication in POAG. In this proposal, using resources from the Nurses Health Study (NHS), we will compare circulating estrogen levels in postmenopausal women with and without POAG. Age at menopause has a genetic basis, and later age has been associated with reduced risk of POAG. Using data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), we will evaluate whether a genetic predisposition score related to age at menopause is associated with POAG. Finally, we will also assess whether specific genotypes in the estrogen metabolic pathway interact with serum estrogen levels in POAG. Our data indicate that genomic variants in CAV1/CAV2, which codes for caveolins juxtaposed to NO synthase 3 (NOS3) in endothelial cell membranes, are related to POAG. Statin use may modulate the functional interaction between caveolin and NO signaling in endothelial cells to favorably alter glaucoma risk. We will perform a prospective cohort analysis of the relation between current statin use and POAG in NHS, NHS2 and the Health Professionals Follow-up Study (HPFS). We will also evaluate whether statin use interacts with common variants of CAV1/CAV2 and NOS3 in POAG. We will extend our analysis of environmental factors related to endothelial cell function to dietary bioflavonoids, which are known to alter endothelial cell function. There is evidence that POAG patients with initial paracentral visual field loss have endothelial cell dysfunction, yet little is known regarding environmental determinants of paracentral visual field loss in POAG. We have discovered two genetic biomarkers of endothelial cell dysfunction in POAG patients with paracentral visual field loss: CAV1/CAV2, GUCY1A3 / GUCY1B3. We will assess if factors that alter endothelial cell function, such as hypertension and postmenopausal hormone use, are associated with this glaucoma endophenotype. POAG is disease with a complex web of pathology. This proposal draws on the wealth of biomarkers related to endothelial cell dysfunction and estrogen metabolism in NHS, NHSII, HPFS and the NEIGHBORHOOD to dis- entangle that web. The proposal aims to identify and develop more rational preventive strategies and interventions for POAG.